Novel dodecyl-containing azido and glucuronamide-based nucleosides exhibiting anticancer potential

Xavier, Nuno M.; Gonçalves-Pereira, Rita; Jorda, Radek; Hendrychová, Denisa; Oliveira, M. Conceição

doi:10.1515/pac-2019-0106

Cited by 11 publications

(29 citation statements)

References 34 publications

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“…The synthesis of 3′- O -dodecyl xylofuranos-5′-yl isonucleosides was based on the Mitsunobu coupling between the 3′- O -dodecyl-1,2- O -isopropylidene xylofuranose precursor ( 2 ), which was prepared from 3′- O -dodecyl-1,2- O -isopropylidene glucofuranose ( 1 ) [19], with purine derivatives and uracil in the presence of diethyl azodicarboxylate (DEAD) and triphenylphosphine (Scheme 1). The reaction with the purine alkaloid theobromine in THF at 50 °C during 2 days led to the desired isonucleoside 3 in a low yield (16%).…”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives

et al. 2019

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Isonucleosides are rather stable regioisomeric analogs of nucleosides with broad therapeutic potential. We have previously demonstrated the ability of 5′ and 6′-isonucleosides to inhibit the activity of acetylcholinesterase, a major target for Alzheimer’s disease therapy. Continuing with our research on this topic, we report herein on the synthesis and biological evaluation of a variety of novel terminal isonucleosides and theobromine isonucleotide analogs. Xylofuranose-based purine or uracil 5′-isonucleosides and xylofuranos-5′-yl or glucos-6′-yl theobromine derivatives were accessed via Mitsunobu coupling between partially protected xylofuranose or glucofuranose derivatives with a nucleobase using conventional or microwave-assisted heating conditions. Theobromine-containing N-isonucleosidyl sulfonamide and phosphoramidate derivatives were synthesized from isonucleosidyl acetate precursors. The most active compounds in the cholinesterase inhibition assays were a glucopyranose-based theobromine isonucleosidyl acetate, acting as a dual inhibitor of acetylcholinesterase (AChE, Ki = 3.1 µM) and butyrylcholinesterase (BChE, Ki = 5.4 µM), and a 2-O,4-O-bis-xylofuranos-5′-yl uracil derivative, which displayed moderate inhibition of AChE (Ki = 17.5 µM). Docking studies revealed that the active molecules are positioned at the gorge entrance and at the active site of AChE. None of the compounds revealed cytoxic activity to cancer cells as well as to non-malignant mouse fibroblasts.

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Section: Resultsmentioning

confidence: 99%

“…soln. ), room temp., 2.5 h, 79% [19]; ( b ) NaBH 4 , EtOH/H 2 O, room temp., 1 h, 81% [19]; ( c ) theobromine, PPh 3 , diethyl azodicarboxylate (DEAD), THF, 50 °C, 48 h, 16% or THF/DMF, MW, max. 150 W, 65 °C, 30 min, 44%; ( d ) adenine, PPh 3 , DEAD, THF/DMF, MW, max.…”

Section: Figures Schemes and Tablementioning

confidence: 99%

Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives

et al. 2019

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“…soln. ), r. t., 2.5-4 h; (b) NaBH4, EtOH/H2O (2/1), r. t., 1 h, 58 (5), 57% (6) [47], 64% (7) [48], 82% (8) [49], 2 steps; (c) TsCl, CH2Cl2/pyridine (1:1, from 7), pyridine (from 8), r. t., 16 h; (d) NaN3, DMF, 80 °C, 16 h, 77 % (14) [48], 80% (15) [47], 2 steps; (d) DPPA, DBU, toluene, r. t., 16 h (from 5), 24 h, then 40°C, 16 h (from 6), 98% (9), 68 % (10) [47]; (e) RBr, NaH, DMF, r. t., 16 h (for R = C3H5), 5 min. (for R = C3H3), 87% (12), 95 % (13) [47].…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

Xavier

Fortuna

Gonçalves-Pereira

et al. 2021

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The synthesis of novel guanidino sugars as potential mimetics of nucleosides and their biological evaluation is described. 5-Guanidino xylofuranoses containing different Osubstituents at C-3, including saturated/unsaturated hydrocarbon chains and aromaticcontaining moieties, were accessed from 5-azido xylofuranose precursors through reduction followed by guanidinylation of the obtained amines with N,N′-bis(tertbutoxycarbonyl)-N′′-triflylguanidine. A 5-azido 3-O-methyl-branched N-benzyltriazole isonucleoside was converted into the corresponding 5-guanidino-containing isonucleoside, whose structure includes both the guanidine and triazole moieties as nucleobase-like motifs connected to the xylofuranose template. In alternative, this structurally new type of compound was synthesized via cycloaddition between a 5guanidino-3-O-propargyl xylofuranose derivative and benzyl azide in the presence of a CuI/Amberlyst A-21 catalytic system, along with the 5-iodotriazole derivative as a secondary product, which, in turn was the sole product when using equimolar CuI and a catalytic amount of 4-dimethylaminopyridine. A guanidinomethyltriazole 3′-O-dodecyl xylofuranos-5′-yl isonucleoside, which comprise a novel isonucleosidic framework having a guanidine system appended on the sugar-linked triazole motif, was obtained from the related aminomethyltriazole 5'-isonucleoside via guanidinylation. Bioactivity screening revealed 2 compounds as selective inhibitors of acetylcholinesterase (AChE), namely the guanidinomethyltriazole derivative, with moderate inhibition (Ki = 22.87 µM) and the 3-O-dodecyl (N-Boc)guanidino xylofuranose, which was the most active compound (Ki = 7.49 µM) acting as a non-competitive inhibitor. The latter also displayed moderate antiproliferative effects in chronic myeloid leukemia (K562, GI50 =31.02 μM) and in breast cancer (MCF-7, GI50 = 26.89 μM) cells. The aminomethyltriazole 5'isonucleoside was the most potent molecule with single-digit micromolar GI50 values against both cells (GI50 = 6.33 μM and 8.45 μM), similar to that of the standard drug 5fluorouracil against MCF-7 cells.

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“…The synthesis of 3-O-substituted 5-guanidino xylofuranose derivatives involved the access to 5-azido precursors, which could be achieved by different pathways depending on the 3-O-substituent (Scheme 1). One pathway involved the oxidative cleavage of 3-Oallyl, -propargyl [47], -dodecyl [48] and -benzyl [49] 1,2-O-isopropylidene glucofuranose derivatives (1-4) with sodium metaperiodate, followed by reduction with sodium borohydride to afford the corresponding xylofuranose derivatives 5-8 for further installation of the azide functionality. This was firstly attempted by a sequence of tosylation (tosyl chloride/pyridine) and further nucleophilic replacement with sodium azide, by which the 3-O-dodecyl and 3-O-benzyl 1,2-O-isopropylidene xylofuranoses 7-8 were converted into 14-15 as previously reported [47,48].…”

Section: Chemistrymentioning

confidence: 99%

“…One pathway involved the oxidative cleavage of 3-Oallyl, -propargyl [47], -dodecyl [48] and -benzyl [49] 1,2-O-isopropylidene glucofuranose derivatives (1-4) with sodium metaperiodate, followed by reduction with sodium borohydride to afford the corresponding xylofuranose derivatives 5-8 for further installation of the azide functionality. This was firstly attempted by a sequence of tosylation (tosyl chloride/pyridine) and further nucleophilic replacement with sodium azide, by which the 3-O-dodecyl and 3-O-benzyl 1,2-O-isopropylidene xylofuranoses 7-8 were converted into 14-15 as previously reported [47,48]. In the case of the allyl and propargyl derivatives 5-6, the corresponding intermediate 5-tosylates were reverted to the 5-hydroxyl derivatives upon treatment with the azide anion.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

Xavier

Fortuna

Gonçalves-Pereira

et al. 2021

Preprint

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The synthesis of novel guanidino sugars as potential mimetics of nucleosides and their biological evaluation is described. 5-Guanidino xylofuranoses containing different O-substituents at C-3, including saturated/unsaturated hydrocarbon chains and aromatic-containing moieties, were accessed from 5-azido xylofuranose precursors through reduction followed by guanidinylation of the obtained amines with N,N′-bis(tert-butoxycarbonyl)-N′′-triflylguanidine. A 5-azido 3-O-methyl-branched N-benzyltriazole isonucleoside was converted into the corresponding 5-guanidino-containing isonucleoside, whose structure includes both the guanidine and triazole moieties as nucleobase-like motifs connected to the xylofuranose template. In alternative, this structurally new type of compound was synthesized via cycloaddition between a 5-guanidino-3-O-propargyl xylofuranose derivative and benzyl azide in the presence of a CuI/Amberlyst A-21 catalytic system, along with the 5-iodotriazole derivative as a secondary product, which, in turn was the sole product when using equimolar CuI and a catalytic amount of 4-dimethylaminopyridine. A guanidinomethyltriazole 3′-O-dodecyl xylofuranos-5′-yl isonucleoside, which comprise a novel isonucleosidic framework having a guanidine system appended on the sugar-linked triazole motif, was obtained from the related aminomethyltriazole 5’-isonucleoside via guanidinylation. Bioactivity screening revealed 2 compounds as selective inhibitors of acetylcholinesterase (AChE), namely the guanidinomethyltriazole derivative, with moderate inhibition (Ki = 22.87 µM) and the 3-O-dodecyl (N-Boc)guanidino xylofuranose, which was the most active compound (Ki = 7.49 µM) acting as a non-competitive inhibitor. The latter also displayed moderate antiproliferative effects in chronic myeloid leukemia (K562, GI50 =31.02 μM) and in breast cancer (MCF-7, GI50 = 26.89 μM) cells. The aminomethyltriazole 5’-isonucleoside was the most potent molecule with single-digit micromolar GI50 values against both cells (GI50 = 6.33 μM and 8.45 μM), similar to that of the standard drug 5-fluorouracil against MCF-7 cells.

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Novel dodecyl-containing azido and glucuronamide-based nucleosides exhibiting anticancer potential

Cited by 11 publications

References 34 publications

Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives

Synthesis and Biological Evaluation of Structurally Varied 5′-/6′-Isonucleosides and Theobromine-Containing N-Isonucleosidyl Derivatives

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

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